Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.[CH3:20][C:21]([CH:24]=O)([CH3:23])[CH3:22].CC1C=CC(S(O)(=O)=O)=CC=1.O>>[N:11]1([CH:20]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CC(C)(C)C=O
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: c1ccc2[nH]nnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)(C)C(NC(=O)c1ccc(Br)cc1)n1nnc2ccccc21

Procedure:
A mixture of 4-bromobenzamide 118 (0.73 g, 3.54 mmol), benzotriazole (0.42 g, 3.52 mmol), pivaldehyde (0.8 mL, 7.27 mmol) and pTSA-HOH (about 60 mg) was heated at reflux for 5 hours in a Dean-Stark apparatus. The mixture was concentrated onto silica gel and purified by chromatography (8:2 CH2Cl2:hexanes to CH2Cl2) to give N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-2,2-dimethylpropyl)-4-bromobenzamide 120 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(OC(C)C)(C)C>[CH3:19][N:20]([CH3:25])[S:21]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:23])=[O:22]
Reactant: OCCOc1ccc(Cl)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis Inc., Windham, N.H. 03087) in 64.6 g (0.640 mole) of triethylamine and 40 ml of methylene chloride was added in a thin stream to a solution of 83.3 g (0.580 mole) of dimethylsulfamoyl chloride (Aldrich) in 60 ml of methylene chloride stirred at ambient temperature in a water bath. The reaction mixture was stirred for 8 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The organic layer was washed with two 200 ml portions of 2N hydrochloric acid. Once with 200 ml of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a viscous residue. The residue was treated with 65.0 g (0.63 mole) of triethylamine and the reaction mixture was stirred for 5 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure and the viscous residue was partitioned between water and ethyl ether (450 ml each). The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a brown viscous oily residue. The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to yield a viscous oil. The oil was dissolved in 150 ml of isopropyl ether and filtered to remove some insolubles. The filtrate was concentrated to a viscous oil. The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.), cooled (refrigerator) and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl ether to give 18.5 g (45%) of white solid, mp 54°-57° C.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[CH:15]3[CH2:16][CH2:17][CH2:18][CH:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>BrC1C=CC=CC=1.[Cu]I>[C:2]1([N:12]2[C:13](=[O:19])[CH:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[N:9]([C:7](=[O:8])[CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]2=3)[CH:3]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)C2CCCC12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(c2ccccc2)C(=O)C2CCCC21
Yield: 126 %

Procedure:
To a suspension of 4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (584 mg, 1.5 mmol) and potassium carbonate (228 mg, 1.6 mmol) in bromobenzene (3 mL) was added copper (I) iodide (57 mg, 0.3 mmol), and the mixture was heated for 90 minutes under reflux. To the reaction mixture was added chloroform, which was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-ethanol-hexane to give 440 mg (yield 63%) of a mixture of cis-compound and trans-compound (3:2), m.p. 272°-273° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:14](=O)[CH2:15][O:16][CH2:17][CH2:18][N:19]=[N+:20]=[N-:21])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[CH3:2].S(O)(O)(=O)=O.[CH3:29][O:30][C:31](=[NH:33])[NH2:32].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[NH:33][C:31]([O:30][CH3:29])=[N:32][C:14]=1[CH2:15][O:16][CH2:17][CH2:18][N:19]=[N+:20]=[N-:21])=[O:23])[CH3:2]
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])N=C(OC)NC1c1ccccc1Cl
Temperature: 80 °C

Procedure:
A mixture of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (1.50 g, 4.44 mmol), O-methylisourea sulfate (0.82 g, 6.66 mmol) and sodium bicarbonate (1.5 g, 17.86 mmol) in N,N-dimethylacetamide (25 mL) was heated to 80° C. and maintained at this temperature overnight (ca. 15 h). The mixture was cooled to RT and then taken up in EtOAc (100 mL) and H2O (50 mL). The EtOAc extract was washed with brine (50 mL), dried (Na2SO4), filtered, concentrated and dried in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 g Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 1.189 g (68% for 2 steps) of white solid as a purified product.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)=O.[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Br)[CH3:13]>>[CH2:12]([O:14][C:15]([CH2:16][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])=[O:18])[CH3:13]
Reactant: Oc1cccnc1O
Reactant: CCOC(=O)CBr
Agent: O=C=O
Product: CCOC(=O)Cn1cccc(O)c1=O
Temperature: 140 °C

Procedure:
2,3-Dihydroxypyridine (10 g) is suspended in ethylbromoacetate (40 ml) and the mixture is heated in a sealed tube for 24 hours at 140° C. The tube is then cooled in solid CO2 and opened. The contents are subjected to rotary evaporation at 50° C. to yield a yellow solid. Recrystallisation of this solid from water yields 1-ethoxycarbonylmethyl-3-hydroxypyrid-2-one as white crystals (10.8 g), m.p. 141°-151° C.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:16])([F:15])[O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:19][C:20](=O)[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[C:24]([Cl:29])=[N:23][CH:22]=1)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][C:21]([C:20]([NH:12][C:11]2[CH:13]=[CH:14][C:8]([O:7][C:6]([F:15])([F:16])[F:5])=[CH:9][CH:10]=2)=[O:19])=[CH:22][N:23]=1
Reactant: CCOC(=O)c1cnc(Cl)c(C#N)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution trimethylaluminium 2 M in toluene (20.77 mL, 41.5 mmol) was added to a stirred solution of 4-(trifluoromethoxy)aniline (2.247 mL, 16.62 mmol) in toluene (150 mL) under an argon atmosphere. After 30 min, a solution of 6-chloro-5-cyanonicotinic acid ethyl ester (3.5 g, 16.62 mmol) in toluene (10 mL) was added and the RM was stirred at 25° C. for 1 h. After cooling to 5° C., the RM was treated dropwise with a solution of sat. aq. NH4Cl (50 mL) and EtOAc (50 mL) was added. The mixture was stirred for 60 min, filtered over Hyflo® and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc, from 0 to 30% EtOAc) and recrystallized from n-hexane/DCM to afford the title compound as a yellow crystalline solid. m.p. 198-200° C., HPLC (Condition 4) tR=6.24 min, UPLC-MS (Condition 8) tR=1.14 min, m/z=340.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.15-7.34 (m, 2H), 7.67 (d, J=8.99 Hz, 2H), 8.02 (br. s, 1H), 8.53 (d, J=2.35 Hz, 1H), 9.05 (d, J=2.35 Hz, 1H).
Reaction SMILES: CC(O)=O.O.[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[N+:16]([O-])=O)[CH2:12][CH2:11][CH2:10]2>CCO.[Fe]>[CH3:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[NH2:16])[CH2:12][CH2:11][CH2:10]2
Reactant: Cc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1N)CCC2
Temperature: 90 °C

Procedure:
5-Amino-6-nitroindane (4 g) is dissolved in 10 mL of MeOH, 30 mL of H2O and 20 mL of H2SO4, and cooled to 0° C. A solution of 1.72 g of NaNO2 (24.9 mmol) in 5 mL of H2O is added dropwise, keeping the temperature of the reaction below 8° C. The mixture is allowed to stir for 30 minutes. This mixture is then added dropwise to a mixture of CuBr (1.8 g, 12.5 mmol) and 6 mL of 48% HBr in 30 mL of H2O that is heated to 60° C. The reaction is cooled and added to H2O and EtOAc. The organic layer is separated and the solvents evaporated in vacuo to give a residue that is purified by silica gel chromatography (75% hexane/EtOAc) to give 5-bromo-6-nitroindane. A mixture of this indane (2.59 g, 12.2 mmol), 4.88 g (27.2 mmol) of tetramethyltin, 0.1 g of Pd(OAc)2 (0.45 mmol), 0.3 g (O-tol) 3P (0.98 mmol), 7 mL of Et3N and 7 mL of DMF is heated in a sealed tube to 65° C. for 3 days. The mixture is acidified with 1 N HCl and extracted with EtOAc. The organic layer is washed with saturated brine and dried over Na2SO4 and the solvents are evaporated in vacuo to give a residue that is purified by column chromatography (80% hexane/EtOAc) to give 5-methyl-6-nitroindane. To a mixture of 1.3 mL of HOAc and 7.3 mL of H2O heated to 90° C. is added 2.22 g of Fe. The mixture is heated until the gas evolution subsides. A solution of 1.9 g of 5-methyl-6-nitroindane (10.7 mmol) in 50 mL of EtOH is added dropwise and the reaction is heated to reflux for 30 minutes. The mixture is extracted twice with CH2Cl2. The combined organic layers are washed with saturated brine and dried over Na2SO4 and the solvents evaporated in vacuo to give a residue that is purified by column chromatography (75% hexane EtOAc) to give 6-methyl-5-aminoindane (also named 5-methyl-6-aminoindane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Sn:15]([CH3:17])([CH3:16])[CH3:14])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: C[Sn](C)(C)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.02 h
Yield: 64.9 %

Procedure:
3.0 g (13 mmol) of p-dibromobenzene was dissolved in 100 ml of anhydrous diethyl ether, and under room temperature and an argon stream, 8.0 ml (13 mmol) of 1.6M n-butyllithium (hexane solution) was gradually added dropwise, followed by stirring for 1 minute. Further, 2.8 g (14 mmol) of trimethyltin chloride was added, and refluxed at 50° C. for 2 hours. After the reaction, the reaction solution was cooled, saturated ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate and anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give 2.7 g of 4-bromophenyltrimethyltin as a colorless oil (yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7].[I:20]Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:11]([I:20])=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: ClI
Reactant: ON=Cc1cc(Cl)ncc1C#Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [O-][n+]1cc2cc(Cl)ncc2c(I)c1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a slurry of 2-chloro-5-((2-chlorophenyl)ethynyl)isonicotinaldehyde oxime (850 mg, 2.9 mmol) in acetonitrile (8 mL) was added iodine monochloride (1.4 g, 8.8 mmol). The reaction mixture instantly became homogeneous and was stirred at room temperature. After 15 minutes the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange residue that was used in the next step without further purification (1.2 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[C:23]([N:27]1[N:31]=[N:30][C:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH:34]=O)=[N:28]1)([CH3:26])([CH3:25])[CH3:24]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[C:29]4[N:30]=[N:31][N:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:28]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CC(C)(C)n1nnc(-c2ccccc2C=O)n1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)n1nnc(-c2ccccc2C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 521 mg (2.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 343 μl of acetic acid are dissolved in 50 ml of methanol and reacted with 691 mg (3.0 mmol) of 2-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde to form 4-(3-chloro-phenylamino)-3-[(2-(2-tert-butyl-tetrazol-5-yl)-phenyl}-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 30 ml of DMEU with 16 ml (16 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino)-3-[2-(2-tert-butyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4d]pyrimidine; TLC: Rf=0.64 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=10.3.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(C(OC)=O)C=C(NCC2CCCC2)N=1.[NH2:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:39][C:40]3[CH:47]=[CH:46][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(CO)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Agent: COC(=O)c1cc(NCC2CCCC2)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A solution of 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13, 1.00 g; 3.63 mmol) in dry DMF (100 ml) was treated with polymer-supported Mukaiyama reagent, prepared as described in “S. Crosignani et al. Org. Lett. 2004, 6(24), 4579-4582” (2 987 mg; 6.54 mmol), 4-aminobenzyl alcohol (Fluka, 492 mg; 3.99 mmol) and triethylamine (1.52 ml; 10.9 mmol). The reaction mixture was then stirred at room temperature for 18 hours. DCM was added and the product was filtered through an SPE column (Isolute NH2, 10 g) and the column washed with DCM. The mixture was concentrated then rediluted in AcOEt. The organic phase was washed 5 times with brine, dried over MgSO4 and the solvent removed under vacuum to give the title compound (990 mg, 72%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1.Cl.[NH2:17][OH:18].O>CN1CCCC1=O>[OH:1][CH2:2][CH2:3][O:4][N:5]=[C:6]1[C:10](=[N:17][OH:18])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1
Reactant: O=C1C(=NOCCO)Oc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCON=C1Oc2ccccc2C1=NO
Yield: 37.8 %

Procedure:
At 80° C., 10.1 g (0.05 mol) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) in 50 ml of N-methyl-2-pyrrolidinone are stirred with 3.5 g of hydroxylamine hydrochloride for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is then chromatographed over silica gel using tert-butyl methyl ether/petroleum ether (1:1). The eluent is distilled off under reduced pressure, affording 4.2 g (29.6% of theory) of benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime]3-oxime consisting of 62.4% of isomer A and 15.8% of isomer B (HPLC).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21](=O)[NH2:22])[C:15]=2[O:14][N:13]=1)=O)(C)(C)C.P(Cl)(Cl)([Cl:26])=O>CN(C)C=O>[ClH:26].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:21]#[N:22])[C:15]=2[O:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1noc2c(C(N)=O)cccc12
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1cccc2c(OCCN)noc12
Temperature: 5 °C
Yield: 120.7 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-7-carbamoyl-1,2-benzisoxazole (0.10 g) in dimethylformamide (1.0 ml) was added phosphorus oxychloride (0.06 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.09 g, 90%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[CH2:13]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)[CH2:14][CH2:15][CH3:16]>C(=S)=S>[CH2:13]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[C:21]=1[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1C
Solvent: S=C=S
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C

Procedure:
To a cooled, stirred solution of 10.8 g. (0.058 mol.) of 3-methyl-4-methoxybenzoic acid chloride and 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran in 40 ml. of carbon disulfide was added dropwise over a 20 minute interval 28.2 g. (0.108 mol.) of stannic chloride. After addition, the reaction mixture was warmed to ambient temperature and stirred for two hours. The mixture was then poured onto 100 ml. of ice-water and stirred for one hour. The solvent was removed, the product extracted into chloroform and the extracts were washed with water, dried (Na2SO4) and concentrated in vacuo to give 2-n-butyl-3-(3'-methyl-4'-methoxybenzoyl)benzofuran.
Reaction SMILES: FC1C(=O)NC(=O)NC=1.C(I)C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:21]1[CH:28]=[C:27]([F:29])[C:25](=[O:26])[N:24](CC)[C:22]1=[O:23])[CH3:20]>CC(C)=O>[CH2:19]([N:21]1[CH:28]=[C:27]([F:29])[C:25](=[O:26])[NH:24][C:22]1=[O:23])[CH3:20]
Reactant: CCn1cc(F)c(=O)n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCI
Product: CCn1cc(F)c(=O)[nH]c1=O

Procedure:
5-fluorouracil, namely Compound (5), (1.30 g; 10 mmol), ethyl iodide (2.34 g; 15 mmol) and potassium carbonate (0.69 g; 5 mmol) were added to acetone (20 ml). The resulting mixture was processed in the same manner as in Example 4 (a) to isolate 1-ethyl-5-fluorouracil, namely Compound (7) (316 mg), and 1,3-diethyl-5-fluorouracil, namely Compound (8) (232 mg), respectively, as white-colored needles.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1Cl)N.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22](=[O:23])[CH2:21][S:20][CH2:19]2)[CH:14]=[CH:15][C:16]=1[Cl:17].C1NCSC1=O.S(Cl)(Cl)=O>>[Cl:1][CH:21]1[S:20][CH2:19][N:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[C:22]1=[O:23]
Reactant: O=C1CSCN1c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1CNCS1
Solvent: O=S(Cl)Cl
Product: O=C1C(Cl)SCN1c1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloroaniline was converted to 3-(3,4-dichlorophenyl)-4-thiazolidinone as outlined in Example 1. This thiazolidinone, which had a melting point of 145°-146° C., was chlorinated with thionyl chloride to form 5-chloro-3-(3,4-dichlorophenyl)-4-thiazolidinone having a melting point of 100°-103° C. Recrystallization of this product from ethanol gave 3-(3,4-dichlorophenyl)-5-ethoxy-4-thiazolidinone which had a melting point of 61°-65° C.
Reaction SMILES: [S:1](N)([NH2:4])(=[O:3])=[O:2].[CH:6]1([CH2:9][NH:10][CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:8][CH2:7]1.C(Cl)Cl>O1CCOCC1>[CH:6]1([CH2:9][N:10]([CH2:11][CH:12]([O:13][CH3:14])[O:15][CH3:16])[S:1]([NH2:4])(=[O:3])=[O:2])[CH2:7][CH2:8]1
Reactant: NS(N)(=O)=O
Reactant: COC(CNCC1CC1)OC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(CN(CC1CC1)S(N)(=O)=O)OC
Yield: 68 %

Procedure:
Sulfamide (5 eq) was added to a solution of N-(cyclopropylmethyl)-(2,2-dimethoxyethanamine) in dioxane (0.12 M). The reaction was stirred at reflux overnight. The solvent was removed in vacuo, the residue taken up in EtOAc and washed with H2O, brine, before being dried (Na2SO4), filtered and concentrated in vacuo to give the crude material. DCM was added and the resultant precipitate removed by filtration, while the filtrate was concentrated in vacuo to afford the product (68%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 0.15-0.19 (m, 2H), 0.44-0.47 (m, 2H), 1.03-1.05 (m, 1H), 2.95-2.98 (m, 2H), 3.17-3.19 (m, 2H), 3.28 (s, 6H), 4.51 (t, J 5.0, 1H), 6.63 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:32])([CH3:31])NC(=O)C.[Br:33]N1C(=O)CCC1=O>ClCCl>[Br:33][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:32])([CH3:31])[CH3:25])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 46 %

Procedure:
To a refluxing suspension of 359 mg (1.03 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, 189 mg of N-trimethylsilylacetamide (1.45 mmoles) were added and the clear solution that was obtained after refluxing for 3/4 hours was cooled in an ice-bath and diluted to 40 ml with dichloromethane. Bromination was carried out in half an hour using 287 mg (1.61 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 46% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.